The locus coeruleus (LC) is the largest noradrenergic (NA) cell group in the central nervous system. In the human LC, there is extensive cell loss with normal aging. Premature loss of LC neurons is particularly dramatic in Parkinson;s disease and in Alzheimer's disease. The mechanisms underlying the LC neuron death are not known. We have recently found that a single systemic injection of the NA neurotoxin DSP-4 into rats causes rapid and profound depletion of norepinephrine (NE) from LC axons. This depletion of neurotransmitter is followed by degeneration of LC axons within two weeks and by loss of more than 50% of the cells in the LC 6 and 12 months after DSP-4 administration. Regeneration of NA axons occurs in forebrain regions previously depleted by DSP-4 but not in brainstem regions, cerebellum and spinal cord. The goals of this application are to characterize the relationship between the DSP-4 induced depletion of NE, NA axon degeneration and NA neuron loss, and to explore the mechanisms that underlie DSP-4 induced LC neuron death. We propose three sets of experiments: (1) To describe the onset and progression of NA neuron loss, we will count cells in all NA subgroups between 1 and 18 months after DSP-4 treatment. For identification of NA neurons we will use dopamine-B-hydroxylase degeneration, NA axon regeneration and LC neuron loss, we will label specific subsets into either frontal cortex, thalamus, cerebellum or spinal cord. Two weeks thereafter, rats will be injected with either DSP-4 or saline and the fate of retrogradely labeled NA neurons will be determined 6 months later by examining a tight linkage between the DSP-4 induced NE depletion and LC axon degeneration, we propose that NE itself and radicals formed during oxidative deamination of NE play role in the neurotoxicity of DSP-4. We will test this hypothesis by determining whether the rate and extent of NA axon degeneration and NA neuron loss after DSP-4 can be influenced by pretreatment with drugs that alter intracellular levels of NE and by drugs that reduce the levels of glutathione in the central nervous system.